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Image Guided Surgery for Margin Assessment of Head and Neck Cancer Using Cetuximab-IRDye800CW cONjugate (ICON)

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ClinicalTrials.gov Identifier: NCT03134846
Recruitment Status : Recruiting
First Posted : May 1, 2017
Last Update Posted : May 3, 2021
Sponsor:
Collaborators:
UMC Utrecht
Erasmus Medical Center
Information provided by (Responsible Party):
dr. M.J.H. Witjes, University Medical Center Groningen

Brief Summary:
Surgery remains a main pillar in the treatment of head and neck squamous cell carcinoma (HNSCC). The margin status is the main prognostic factor of local tumor control in surgically treated HNSCC and will determine the postoperative treatment strategy. A margin of ≤1 mm of normal tissue is considered a positive margin and requires either a re-operation or postoperative chemoradiation with a combination of cisplatin and 5-FU, which substantially increases morbidity. Margins wider than 1 mm but less than 5 mm require re-operation, or, if that is not possible, post-operative radiotherapy without the concomitant use of chemotherapy. Currently, no technology is available in the operating room, which reliably supports tumor excision in terms of margin status. In fact, surgeons can only combine pre- operative imaging data with tactile and visual information during surgery for assessing tumor margins with limited accuracy. With the introduction of molecular imaging techniques using near infrared (NIR) fluorescent optical contrast agents coupled to targeted compounds, new avenues have opened up for intra-operative assessment of tumor margins. Tracers are based on antibodies directed against Vascular Endothelial Growth Factor-A, i.e. bevacizumab-IRDye800CW, in patients with breast cancer or against Epidermal Growth Factor Receptor, i.e. cetuximab-IRDye800CW, in patients with HNSCC. First trials have shown that systemic administration of these compounds is safe and tumor specific. These findings prompted us to design this innovative application in a clinical trial for the intraoperative assessment of tumor margins during surgical treatment of HNSCC using cetuximab-IRDye800CW.

Condition or disease Intervention/treatment Phase
Head and Neck Squamous Cell Carcinoma Margin Assessment Drug: Cetuximab-IRDye800CW Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 79 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Phase 1: 3x3 Dose-escalation with 3 different doses Cetuximab-IRDye800CW Phase 2: Prospective cross sectional diagnostic study. After having established the optimal cetuximab-IRDye800CW dose we will extent the study by including up to 70 patients.
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Image Guided Surgery for Margin Assessment of Head and Neck Cancer Using Cetuximab-IRDye800CW cONjugate
Actual Study Start Date : December 16, 2017
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : June 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Cetuximab

Arm Intervention/treatment
Experimental: Phase 1: 10mg Cetuximab-IRDye800CW
Three patients will receive 10mg Cetuximab-IRDye800cv I.V. four days prior to surgery.
Drug: Cetuximab-IRDye800CW
Pre-operatively administration of Cetuximab-IRDye800CW for intra operative margin assessment using a fluorescent antibody-based optical tracer
Other Name: Cetuximab-800cw

Experimental: Phase 1: 25mg Cetuximab-IRDye800CW
Patients will receive 25mg Cetuximab-IRDye800cv I.V. four days prior to surgery.
Drug: Cetuximab-IRDye800CW
Pre-operatively administration of Cetuximab-IRDye800CW for intra operative margin assessment using a fluorescent antibody-based optical tracer
Other Name: Cetuximab-800cw

Experimental: Phase 1: 50 mg Cetuximab-IRDye800CW
Patients will receive 50mg Cetuximab-IRDye800cv I.V. four days prior to surgery.
Drug: Cetuximab-IRDye800CW
Pre-operatively administration of Cetuximab-IRDye800CW for intra operative margin assessment using a fluorescent antibody-based optical tracer
Other Name: Cetuximab-800cw

Experimental: Phase 1: 75mg cetuximab + 15 mg Cetuximab-IRDye800CW
Patients will receive 75mg cetuximab + 15 mg Cetuximab-IRDye800CW I.V. four days prior to surgery.
Drug: Cetuximab-IRDye800CW
Pre-operatively administration of Cetuximab-IRDye800CW for intra operative margin assessment using a fluorescent antibody-based optical tracer
Other Name: Cetuximab-800cw

Experimental: Phase 1: 75mg cetuximab + 25 mg Cetuximab-IRDye800CW
Patients will receive 75mg cetuximab + 25 mg Cetuximab-IRDye800CW I.V. four days prior to surgery.
Drug: Cetuximab-IRDye800CW
Pre-operatively administration of Cetuximab-IRDye800CW for intra operative margin assessment using a fluorescent antibody-based optical tracer
Other Name: Cetuximab-800cw

Experimental: After having established the optimal cetuximab-IRDye800CW dose
After having established the optimal cetuximab-IRDye800CW dose we will extent the study by including up to 70 patients for this specific dose (as determined in phase 1).
Drug: Cetuximab-IRDye800CW
Pre-operatively administration of Cetuximab-IRDye800CW for intra operative margin assessment using a fluorescent antibody-based optical tracer
Other Name: Cetuximab-800cw




Primary Outcome Measures :
  1. Phase 1: Determine the optimal dose of Cetuximab-IRDye800CW for imaging [ Time Frame: Five months ]
    The primary endpoint for the feasibility study (9 patients) will be confirmation of the clinically applicable dose of cetuximab-IRDye800CW. The aim is to obtain at least a TBR higher than 2 by fluorescence imaging with the intra operative camera. This number has been found to give sufficient demarcation of tumor to normal tissue on wide field images.

  2. Phase 2: Threshold level of fluorescence [ Time Frame: Three years ]
    Determine a threshold level of fluorescence that can discriminate between EGFR distribution in normal tissue and a margin with EGFR-positive tumor.


Secondary Outcome Measures :
  1. Phase 1: Secondary outcome: Safety [ Time Frame: Five months ]
    Adverse events will be monitored

  2. Phase 1: Secondary outcome: Identification of positive margins [ Time Frame: Five months ]
    By ex vivo imaging and MDSFR spectroscopy of the excised specimen

  3. Phase 1: Tissue specificity of IRDye800cw [ Time Frame: Five months ]
    Identification of the tissues that show IRDye800CW-fluorescence in the surgical wound bed after tumor removal

  4. Phase 1: Histological location of IRDye800cw [ Time Frame: Five months ]
    Localisation patterns of cetuximab-IRDye800CW in the tumor and normal tissue by microscopy

  5. Phase 2: Secondary outcome: Minimal thickness of the non-fluorescent margin [ Time Frame: Three years ]
    The assessment of the minimal thickness of the non-fluorescent margin of the excised specimen with histopathology and fluorescence microscopy. This will provide us the first data on the relationship between margin thickness when fluorescence cannot be detected.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria

  1. Biopsy confirmed diagnosis of primary or recurrent HNSCC and scheduled to undergo surgical resection as decided by the Multi-Disciplinary Head and Neck Tumor Board of the UMCG.
  2. Age ≥ 18 years
  3. Written informed consent
  4. Adequate potential for follow up
  5. Acceptable hematologic status, kidney function, and liver function, as standard surgery protocol requires.

Exclusion criteria

  1. Medical or psychiatric conditions that compromise the patient's ability to give informed consent
  2. Concurrent uncontrolled medical conditions.
  3. Received an investigational drug within 30 days prior to the dose of cetuximab-IRDye800CW
  4. Tumors at sites of which the surgeon would assess that in vivo imaging would not be feasible
  5. Had within 6 months prior to enrollment: myocardial infarction, cerebrovascular accident, uncontrolled cardiac heart failure, significant liver disease, unstable angina
  6. Inadequately controlled hypertension with or without current antihypertensive medications.
  7. History of infusion reactions to cetuximab or other monoclonal antibody therapies
  8. Pregnant or lactating women. Documentation of a negative pregnancy test must be available for women of childbearing potential. Woman of childbearing potential are premenopausal women with intact reproductive organs and women less than two years after menopause.
  9. Evidence of QT prolongation on pretreatment ECG (greater than 440 ms in males or greater than 450 ms in females)
  10. Lab values that in the opinion of the primary surgeon would prevent surgical resection.
  11. Patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents.
  12. Magnesium, potassium and calcium lower than the lower limit of normal range.
  13. Life expectancy < 12 weeks
  14. Karnofsky performance status < 70%

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03134846


Contacts
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Contact: Max J.H. Witjes, MD, PhD +31-50-3613841 m.j.h.witjes@umcg.nl
Contact: Floris J. Voskuil, MD +31-50-3655170 f.j.voskuil@umcg.nl

Locations
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Netherlands
University Medical Center Groningen Recruiting
Groningen, Netherlands, 9713 GZ
Contact: Max J.H. Witjes, MD, PhD       m.j.h.witjes@umcg.nl   
Contact: Floris J. Voskuil, MD    +31-50-3610030    f.j.voskuil@umcg.nl   
Sponsors and Collaborators
University Medical Center Groningen
UMC Utrecht
Erasmus Medical Center
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Responsible Party: dr. M.J.H. Witjes, MD, PhD, University Medical Center Groningen
ClinicalTrials.gov Identifier: NCT03134846    
Other Study ID Numbers: NL58585.042.16
First Posted: May 1, 2017    Key Record Dates
Last Update Posted: May 3, 2021
Last Verified: April 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by dr. M.J.H. Witjes, University Medical Center Groningen:
Intraoperative fluorescence imaging
Cetuximab-IRDye800CW
Molecular imaging
Additional relevant MeSH terms:
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Head and Neck Neoplasms
Squamous Cell Carcinoma of Head and Neck
Carcinoma, Squamous Cell
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Cetuximab
Antineoplastic Agents, Immunological
Antineoplastic Agents